Similar to influenza virus, Streptococcus pneumoniae is a pathogen of clinical importance that begins as an upper respiratory tract infection. The pathogenicity arises upon progression to otitis media, pneumonia, bacteremia, or meningitis. The manifestations are severe diseases that would result in death in children and adults.
As a method of preventing such an infection caused by Streptococcus pneumoniae, currently, 7-, 10- and 13-valent polysaccharide conjugate pneumococcal vaccines (PCV7, 10, 13) have been developed for adults and are delivered by intramuscular injection. However, such vaccines based on polysaccharides hardly induce an immune response in children due to low immunogenicity of polysaccharides as a T cell-independent antigen, and exhibit an infection-preventing effect only for Streptococcus pneumoniae of capsular types. Further, intramuscular injection of vaccines mainly induces systemic anti-IgG antibodies, thus causing such a problem that these vaccines fail to induce a mucosal immune response against Streptococcus pneumoniae. 
PspA, the pneumococcal surface protein, is a well-known highly immunogenic protein and is considered to be a promising vaccine candidate (Non-Patent Literatures 1 and 2). It is present on virtually all strains of pneumococci, and PspA-based vaccines induce cross-reactive antibodies in mice and humans (Non-patent Literatures 3-5). Moreover, PspA-specific mucosal and systemic antibody responses are induced, and these responses are mediated by both Th1- and Th2-type cytokine responses by CD4+ T cells in infant mice (via maternal immunization), as well as in aged mice. These findings indicate that PspA is a potent pneumococcal vaccine effective not only in adults but also in children.
Streptococcus pneumoniae of any types colonize the nasal cavity and cause an initial infection on the respiratory tract mucosae, thus a nasal vaccine is expected to be the most effective method for preventing Streptococcus pneumoniae infection.
However, there is currently no safe adjuvant for nasal immunization or delivery system of the nasal vaccine, as evaluated by the so-called safety pharmacology studies, such as absorption, distribution, metabolism and excretion (ADME), in preclinical studies, thus causing one of obstacles for practical application. Further, co-administration of biologically active mucosal adjuvants such as cholera toxin (CT) and heat-labile enterotoxin (LT) is facing concern that toxin may be delivered to the central nervous system or accumulated in the olfactory bulbs and the like. As such, administration of such adjuvants to humans is not very desirable and there are still matters to be solved on safety.
To overcome these concerns, the inventors of the present invention recently developed an effective vaccine delivery system with a self-assembled nanosized hydrogel (nanogel), which is composed of a cationic type of cholesteryl group-bearing pullulan (cCHP) (Patent Document 1, and Non-Patent Literature 6).
cCHP nanogel retains antigen proteins in its nano matrix and functions as an artificial chaperone that prevents antigens from aggregating and denaturing and assists refolding after releasing them. This cCHP nanogel is efficiently delivered to cells, and induces immune responses as an adjuvant-free vaccine (Non-Patent Literature 7, 8, and Patent Document 2). Furthermore, any experimental result did not show that nasally administered cCHP nanogel carrying the [111In]-labeled BoHc/A (non-toxic region of C-terminal heavy chain domain of botulinum neurotoxin type A) accumulates in the central nervous system including an olfactory bulb and a brain in mice (Non-Patent Literature 7). A separate study by the inventors demonstrated that a nasal PspA-nanogel vaccine is safe and induces strong antigen-specific systemic and mucosal antibody immune responses in mice (Non-Patent Literature 9).
As described above, the PspA-nanogel nasal vaccine is very excellent in terms of both safety and induction of protective immunity, and expected to be put in practical application as a nasal vaccine (Non-Patent Document 9). However, the efficacy has not been so far demonstrated in primates and further improvements have to be made for practical application.